Ferric Carboxymaltose Methemoglobinemia Study (FerMet)

Estimation of the Incidence of Methemoglobinemia Associated With Ferric Carboxymaltose Administration

Anemia that develops due to iron deficiency is called iron deficiency anemia. This common condition is treated with iron supplements taken either orally or given through an intravenous (IV) infusion. Ferric carboxymaltose (FCM) is one of the widely used, comparably newer IV iron preparations. Recently, several publications have raised the possibility that FCM may be associated with mild elevations in methemoglobin (metHb), a form of hemoglobin that cannot effectively deliver oxygen to tissues.

Methemoglobinemia is a known, though uncommon, side effect of some drugs. While usually mild and self-limiting, in certain cases it can become clinically significant or even life-threatening. This observational study is being conducted across multiple centers to better understand how often methemoglobinemia occurs after administration of FCM. As part of routine care, venous blood samples will be used to measure metHb levels in patients receiving FCM, and these results will be compared with those from individuals not exposed to the drug.

Study Overview

• Status: Completed
• Conditions: Anemia, Iron-Deficiency; Methemoglobinemia; Parenteral Iron Therapy; Ferric Carboxymaltose
• Intervention / Treatment: Drug: Ferric Carboxymaltose (FCM)

Detailed Description

Methemoglobinemia, which results from the conversion of ferrous iron (Fe2+) to ferric iron (Fe3+) in hemoglobin (Hb), is a potentially life-threatening disorder resulting in functional anemia due to reduced oxygen-carrying capacity. Methemoglobin (metHb) levels above one percent (>1%) are considered abnormal, and ≥3% metHb is considered clinically significant methemoglobinemia. Severe elevation of this level (>20%) leads to more dangerous clinical manifestations such as shortness of breath, confusion, arrhythmias, and seizures. Cases are usually asymptomatic until metHb levels reach 20%, and only discoloration of the blood and/or skin can be detected. Levels exceeding 70 percent are fatal.

The more common acquired form of methemoglobinemia, which can be congenital or acquired, is often caused by the use of drugs or toxic substances. Exposure to certain compounds that exceed the enzymatic reduction capacity of erythrocytes causes signs/symptoms. Benzocaine, phenazopyridine, dapsone, and nitrates/nitrites are the substances most commonly associated with methemoglobinemia.

Ferric carboxymaltose (FCM) is a third-generation intravenous iron drug with a ferric iron (Fe³⁺) compound that is widely used in the intravenous treatment of iron deficiency anemia. There are only three studies on the relationship between FCM and metHb reflected in the literature, one as a case report and two as congress proceedings. Given the expanding clinical use of FCM and the potential implications of undetected methemoglobinemia, there is a need to evaluate this association in a structured and systematic manner under routine care conditions. This study is designed to contribute to pharmacovigilance efforts by generating incidence data and exploring potential patient-related or treatment-related risk factors. Therefore, the investigators plan to determine the incidence of this comparably rare adverse effect with a prospective multicenter observational study.

The primary objective is to estimate the incidence of methemoglobinemia - defined as venous blood methemoglobin (metHb) levels ≥3%-within 30 min. following intravenous administration of ferric carboxymaltose in adult patients receiving routine care.

Secondary objectives include (i) description of the full distribution of metHb values post-infusion (ii) determination of whether metHb levels remain elevated beyond 30 min. in affected individuals, (iii) estimation of the background distribution of metHb levels in an unexposed, healthy outpatient population (iv) comparison of the metHb levels between FCM-exposed patients and unexposed controls (v) identification of potential associations between methemoglobinemia and relevant covariates, including patient demographics, total iron dose administered, baseline hemoglobin and venous oxygen saturation, or other potential oxidant exposures.

This study is a multicenter, prospective observational study. Ferric carboxymaltose recipients are determined based on routine medical care practices; the researchers do not define which participants will receive ferric carboxymaltose. Patient recruitment will take place between April 14, 2025, and September 15, 2025, per protocol, in 21 different health institutions.

Statistical analysis:

Methemoglobinemia rates (≥3% metHb) between the exposed (FCM) and unexposed groups will be compared using Fisher's exact test. Subgroup differences in continuous metHb levels will be analyzed using analysis of variance (ANOVA) with appropriate post hoc comparisons. Correlations between metHb levels and continuous clinical variables will be evaluated using correlation tests. Independent predictors of methemoglobinemia will be assessed through multivariable regression modeling. A two-sided significance threshold of α = 0.05 will be used for all tests.

• Study Type: Observational
• Enrollment (Actual): 977

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Adana
    • Adana, Adana, Turkey (Türkiye), 01100
      • University of Health Sciences Adana City Health Application and Research Center
  • Antalya
    • Konyaalti, Antalya, Turkey (Türkiye), 07070
      • Akdeniz University Hospital
  • Balıkesir
    • Merkez, Balıkesir, Turkey (Türkiye), 10145
      • Balıkesir University Health Practice and Research Hospital
  • Bursa
    • Nilufer, Bursa, Turkey (Türkiye), 16110
      • Bursa City Hospital
  • Diyarbakır
    • Kayapınar, Diyarbakır, Turkey (Türkiye), 21070
      • University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital
  • Istanbul
    • Ataşehir, Istanbul, Turkey (Türkiye), 34758
      • Mehmet Yılmaz Aydınlar Acıbadem University
    • Pendik, Istanbul, Turkey (Türkiye), 34890
      • Marmara University Training and Research Hospital
    • Ümraniye, Istanbul, Turkey (Türkiye), 34764
      • Ümraniye Training and Research Hospital
  • Karabük Province
    • Karabük, Karabük Province, Turkey (Türkiye), 78100
      • Karabuk University Training and Research Hospital
  • Kayseri
    • Kocasinan, Kayseri, Turkey (Türkiye), 38080
      • Kayseri City Hospital
  • Kepez
    • Antalya, Kepez, Turkey (Türkiye), 07080
      • Antalya City Hospital
  • Kestel
    • Bursa, Kestel, Turkey (Türkiye), 16450
      • Bursa Kestel State Hospital
  • Kızıltepe
    • Mardin, Kızıltepe, Turkey (Türkiye), 47400
      • Mardin Kızıltepe State Hospital
  • Mardin
    • Merkez, Mardin, Turkey (Türkiye), 47100
      • Mardin Artuklu University Training and Research Hospital
  • Ordu
    • Altinordu, Ordu, Turkey (Türkiye), 52200
      • Ordu University Training and Research Hospital
  • Rize Province
    • Rize, Rize Province, Turkey (Türkiye), 53100
      • Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital
  • Sakarya
    • Adapazarı, Sakarya, Turkey (Türkiye), 54100
      • Sakarya University Training and Research Hospital
  • Siirt
    • Siirt, Siirt, Turkey (Türkiye), 56100
      • Siirt University Faculty of Medicine Training and Research Hospital
  • Van
    • Merkez, Van, Turkey (Türkiye), 65000
      • Van Yüzüncü Yıl University Training and Research Hospital
  • Yıldırım
    • Bursa, Yıldırım, Turkey (Türkiye), 16310
      • Bursa Yuksek Ihtisas Training and Research
  • Çankırı
    • Çankırı, Çankırı, Turkey (Türkiye), 18100
      • Çankırı State Hospital
  • Çorlu
    • Tekirdağ, Çorlu, Turkey (Türkiye), 59850
      • Çorlu Vatan Hospital
  • İzmir
    • Çiğli, İzmir, Turkey (Türkiye), 35610
      • Izmir Bakircay University Cigli Training and Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Study participants will consist of persons admitted to a total of 21 different secondary or tertiary care hospitals in 16 different provinces across Turkey.

Description

INCLUSION CRITERIA:

FCM Group:

1. Adults (≥18 years)
2. Presence of anemia (Hb <12 g/dl in women, <13 g/dl in men)
3. Low ferritin (<30 mcg/l)
4. Patients for whom FCM administration has been decided in routine medical care practice

Control Group:

Healthy adult (≥18 years) individuals who applied to the internal medicine outpatient clinic, who had no current or pre-existing chronic disease, who did not have anemia and iron deficiency (ferritin ≥30 mcg/L).

EXCLUSION CRITERIA:

1. Known methemoglobinemia-related diseases (Hb M disease, cytochrome b5 reductase deficiency, etc.)
2. Use of drugs associated with methemoglobinemia (acetylsalicylic acid, dapsone, chloroquine, metoclopramide, benzocaine, lidocaine, prilocaine, rasburicase, primaquine, sulfonamide, nitric oxide)
3. Those with B12 and/or folate deficiency
4. Those with Charlson Comorbidity Index ≥3
5. Presence of advanced organ failure (Stage 4 and 5 chronic kidney disease, Child C cirrhosis, NYHA class 3 and 4 chronic heart failure, respiratory failure requiring oxygen supplementation and similar processes)
6. Presence of malignancy (with or without cure)
7. Presence of active infection (CRP > 5 mg/dL) and/or other acute disorder/disease
8. Pregnancy status

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
FCM Group; It will represent the group of patients who will be administered ferric carboxymaltose (FCM), i.e., the exposed group.	Drug: Ferric Carboxymaltose (FCM); As this is an observational study, ferric carboxymaltose recipients are determined based on routine medical care practices. The researchers do not define which participants will receive ferric carboxymaltose.
Control Group; It will represent the control group of patients who do not receive FCM or any form of iron therapy, i.e., the unexposed group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Treatment-Related Clinically Significant Methemoglobinemia	Methemoglobin levels will be measured just before the infusion and at the 15th and 30th minutes post-infusion through venous sampling. The levels equal to or above 3% will be regarded as clinically significant methemoglobinemia.	From the time of enrollment through 30 minutes following completion of the infusion. If methemoglobin level is ≥3% after infusion, blood sampling will continue every half hour after the last blood gas for 24 hours until methemoglobinemia is <3%.

Collaborators and Investigators

• Sponsor: Ordu University
• Collaborators: Marmara University Pendik Training and Research Hospital
• Investigators: Study Director: Muhammet Özbilen, MD, Ordu University Faculty of Medicine; Study Director: Gökhan Tazegül, MD, Marmara University; Study Director: Volkan Aydın, MD PhD, Marmara University School of Dentistry; Principal Investigator: Murat Bahadır, MD, Ordu University Faculty of Medicine, Department of Internal Medicine; Principal Investigator: Bilge Ada Özcan, MD, Marmara University Training and Research Hospital; Principal Investigator: Mehmet Bankir, MD, University of Health Sciences Adana City Health Application and Research Center; Principal Investigator: Mehmet Can Erişen, MD, University of Health Sciences Adana City Health Application and Research Center; Principal Investigator: Nurhayat Özkan Sevencan, MD, Karabuk University Training and Research Hospital; Principal Investigator: Ceren Çevik, MD, Karabuk University Training and Research Hospital; Principal Investigator: Aysel Toçoğlu, MD, Sakarya University Training and Research Hospital; Principal Investigator: Sümeyye Çekiç, MD, Sakarya University Training and Research Hospital; Principal Investigator: Arzu Denler Kılıç, MD, Çankırı State Hospital; Principal Investigator: Mehmet Selim Mamiş, MD, Siirt University Faculty of Medicine Training and Research Hospital; Principal Investigator: Necip Nas, MD, Siirt University Faculty of Medicine Training and Research Hospital; Principal Investigator: Teslime Ayaz, MD, Izmir Bakircay University Cigli Training and Research Hospital; Principal Investigator: Barış Emekdaş, MD, Izmir Bakircay University Cigli Training and Research Hospital; Principal Investigator: İhsan Solmaz, MD, University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital; Principal Investigator: Ömer Faruk Alakuş, MD, University of Health Sciences Diyarbakır Gazi Yaşargil Training and Research Hospital; Principal Investigator: Kamil Konur, MD, Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital; Principal Investigator: Hasan Sözel, MD, Akdeniz University Hospital; Principal Investigator: Esin Avşar Küçükkurt, MD, Akdeniz University Hospital; Principal Investigator: Hacer Şen, MD, Balıkesir University Health Practice and Research Hospital; Principal Investigator: Özge Kama Başçı, MD, Balıkesir University Health Practice and Research Hospital; Principal Investigator: Nizameddin Koca, MD, Bursa City Hospital; Principal Investigator: Fatih İleri, MD, Bursa City Hospital; Principal Investigator: Banu Açmaz, MD, Kayseri City Hospital; Principal Investigator: Erdem Aydın, MD, Kayseri City Hospital; Principal Investigator: İdris Baydar, MD, Mardin Artuklu University Training and Research Hospital; Principal Investigator: Şengül Baran Yerlikaya, MD, Mardin Artuklu University Training and Research Hospital; Principal Investigator: Yıldız Okuturlar, MD, Mehmet Yılmaz Aydınlar Acıbadem University; Principal Investigator: Sibel Serin Ocak, MD, Umraniye Training and Research Hospita; Principal Investigator: Nur Düzen Oflas, MD, Van Yüzüncü Yıl University Training and Research Hospital; Principal Investigator: Abdullah Güneş, MD, Van Yüzüncü Yıl University Training and Research Hospital; Principal Investigator: Nazire Osmançelebioğlu, MD, Recep Tayyip Erdoğan University Faculty of Medicine Training and Research Hospital; Principal Investigator: Ant Uzay, MD, Mehmet Yılmaz Aydınlar Acıbadem University; Principal Investigator: Sevgi Gülşen Koç, MD, Antalya City Hospital; Principal Investigator: Ayşe Karaduru, MD, Antalya City Hospital; Principal Investigator: Gamze Kocaman, MD, Bursa Yuksek Ihtisas Training and Research Hospital; Principal Investigator: Ali Erol, MD, Bursa Yuksek Ihtisas Training and Research Hospital; Principal Investigator: Mehmet Biricik, MD, Mardin Kiziltepe State Hospital; Principal Investigator: Emine Binnetoğlu, MD, Çorlu Vatan Hospital; Principal Investigator: Muhammet Fatih Şahin, MD, Bursa Kestel State Hospital; Principal Investigator: Ebru Çağrı Çakır Özden, MD, Bursa Kestel State Hospital

Publications and helpful links

General Publications

• Tazegul Gokhan, Kimyon Yusuf, Odabasi Zekaver. Ferric carboxymaltose induced methaemoglobinemia: Preliminary data of a novel side effect. 22nd European Congress of Internal Medicine , İstanbul, Turkey, 2024.
• Özbilen M, Savrun ŞT, Aygün A, Kaya Y. P1492: A New Potential And Prevalent Side Effect of Ferric Carboxymaltose: Methemoglobinemia. A Case-Control Study. Hemasphere. 2023 Aug 8;7(Suppl 3):e825173f.
• Ozbilen M, Savrun ST, Aygun A, Kaya Y. Ferric Carboxymaltose-mediated Methemoglobinemia. Curr Drug Saf. 2024;19(1):134-137. doi: 10.2174/1574886318666230213111038.

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2025
• Primary Completion (Actual): September 30, 2025
• Study Completion (Actual): September 30, 2025

Study Registration Dates

• First Submitted: April 13, 2025
• First Submitted That Met QC Criteria: April 26, 2025
• First Posted (Actual): May 6, 2025

Study Record Updates

• Last Update Posted (Actual): November 19, 2025
• Last Update Submitted That Met QC Criteria: November 16, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: iron deficiency anemia; ferric carboxymaltose; intravenous iron; methemoglobinemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Anemia; Iron Metabolism Disorders; Anemia, Hypochromic; Nutritional and Metabolic Diseases; Hemic and Lymphatic Diseases; Iron Deficiencies; Anemia, Iron-Deficiency; Methemoglobinemia; ferric carboxymaltose
• Other Study ID Numbers: 2024-KAEK-30 / 2025-43

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Age, gender, hemoglobin, MCV, MCHC, ferritin, CRP, transferrin saturation, ferric carboxymaltose (FCM) drug dose, FCM infusion concentration, infusion duration, methemoglobin levels
• IPD Sharing Time Frame: Beginning 3 months after publication with no end date

IPD Sharing Access Criteria

De-identified individual participant data (IPD) that underlie the results reported in this article (text, tables, figures, and appendices) will be made available to researchers who provide a methodologically sound proposal in order to achieve aims in the approved proposal.

Access to the IPD will require prior approval from the principal investigator. Researchers will need to submit a formal data access request including:

A detailed research protocol with clear objectives and statistical analysis plan,

A data use agreement,

Proof of institutional ethics approval (if applicable).

Decisions regarding data access will be made by the study's data sharing committee within a reasonable time frame, and applicants will be notified via email.

Requests should be directed to: drozbilen@gmail.com

Data will be shared via a secure data transfer system or repository, depending on the nature and size of the dataset.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No